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Monocyte Subset Predicts Clinical Outcomes in Fibrotic Hypersensitivity Pneumonitis

ABSTRACT: This study aimed to identify circulating immune cell populations associated with disease severity and progression in fibrotic hypersensitivity pneumonitis (fHP). Using single-cell RNA sequencing of peripheral blood mononuclear cells from 33 fHP patients (NCT02958917) and 36 sex-matched healthy controls (GSE196735, pools 1-3), we identified significant shifts in immune cell composition. Compared to controls, fHP patients exhibited a marked increase in classical monocytes (CD14⁺), non-classical monocytes (CD16⁺), and myeloid-derived dendritic cells. Classical monocytes, in particular, were strongly correlated with baseline lung fibrosis severity—quantified by data-driven texture analysis of high-resolution computed tomography—and with reduced progression-free survival. Pathway analysis revealed that monocytes from patients with severe disease were enriched for inflammatory and metabolic processes, whereas those from patients with poor outcomes showed upregulation of interferon and NF-κB signaling. These findings highlight peripheral monocytes as promising prognostic biomarkers in fHP and suggest their role in driving fibrotic progression through dysregulated immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317902 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:Rationale: Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods: Single-cell 5’ RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFb and TNFa/NFkB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions: Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells – reflecting this disease’s unique inflammatory T-cell driven nature – as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Project description:Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has exhibited significant efficacy in the treatment of EGFR-mutated non-small cell lung cancer. Drug-induced interstitial lung disease is a potentially fatal complication of osimertinib therapy. Although there is often an elevated number of lymphocytes in the bronchoalveolar lavage fluid (BALF) in patients with drug-induced pneumonitis, the precise involvement of lymphocytes in osimertinib-induced pneumonitis remains unclear. Therefore, we investigated the pathogenesis of osimertinib-induced pneumonitis using BALF obtained from patients with osimertinib-induced pneumonitis and a mouse model of osimertinib-induced pneumonitis. Methods: Mass cytometry was used to analyze BALF cells obtained from patients with osimertinib-induced pneumonitis. A mouse model of osimertinib-induced pneumonitis was established by the administration of naphthalene and osimertinib. Histopathological evaluation, body weight measurements, BALF analysis, and RNA sequencing were performed to investigate immune cell involvement and the mechanisms underlying osimertinib-induced pneumonitis. Results: Analysis of BALF cells obtained from patients with osimertinib-induced pneumonitis revealed the expansion of CCR7+ CD45RA+ naïve T cells. In the mouse model, osimertinib administration following naphthalene-induced club cell injury exacerbated lung inflammation, leading to increased inflammatory cell infiltration and body weight loss. BALF analysis revealed elevated proportions of T cells, including CD4+ and double-negative T cells, in mice administered osimertinib after naphthalene treatment. Bulk RNA sequencing identified upregulation of chemokine-related biological processes, with increased the expression of C-C motif chemokine ligand 21 (Ccl21) and C-C motif chemokine ligand 8 (Ccl8) in lung tissue, and immunostaining confirmed elevated expression of Ccl21 and Ccl8 in the distal bronchiolar epithelium. Conclusion: This study provides insights into the immune mechanisms underlying osimertinib-induced pneumonitis, which are crucial for overcoming this fatal complication in EGFR-positive non-small cell lung cancer.

Project description:The clinical presentations and outcomes of SARS-CoV-2 infection are highly variable, ranging from asymptomatic infections to severe conditions, and the underlying mechanisms remain largely unknown. In this study, we performed the single-cell RNA sequencing to examine the profiles of the peripheral blood mononuclear cells (PBMCs) from the healthy controls (HC), asymptomatic individuals (AS) and symptomatic COVID-19 patients (SM) with various clinical features and disease severity. We first identified nine major cell types, including T cells, B cells, monocytes, natural killer (NK) cells, dendritic cells (DC), platelets, neutrophils, plasma cells and stem cells from a total of 119,799 single cells captured and filtered for the final analysis, and then divided these cell types into separate cell clusters and sub-clusters, respectively. We revealed that SARS-CoV-2 infection resulted in profound alternations in various cellular compartments and identified a number of distinct immune cell subsets that were associated with various clinical presentations, disease severity and viral persistence of COVID-19. (NCAM1+CD160+) NK cells increased significantly in AS and SM individuals compared with the HC. SM patients showed a significant increase in (LAG3+CD160+CD8+) NKT cells and a decrease in (CD4-CD8-) double negative T cells compared with the AS subjects. (CD68-CSF1R-IL1BhiCD14+) classical monocytes were significantly higher in patients with severe disease (SD) than the patients with moderate disease (MD). (CD68-CSF1R-IL1BhiCD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were positively and negatively correlated with the age-related disease severity of COVID-19 patients, respectively. Increases in (CD33-HLA-DMA-CD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were associated with long-term nucleic acid test positive (LTNP) patients compared with the short-term nucleic acid test positive (STNP) individuals. Increases in (LAG3+CD160+CD8+) NKTcells and (FOXP3+IL2RA+IL7R+CD4+) Treg cells were observed in a patient lacking B cells and plasma cells. Dramatic increases in neutrophils, (CD33-HLA-DMA-CD14+) classical monocytes, and (CD68-CSF1R-IL1BhiCD14+) classical monocytes were detected at a later stage of a fatal patient. Our findings may enhance our understanding of the immune cell alternations involved in the pathogenesis of COVID-19 and the protective immune responses against SARS-CoV-2 infection.

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Monocyte Subset Predicts Clinical Outcomes in Fibrotic Hypersensitivity Pneumonitis

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